Alzheimer's disease is the most common type of dementia experienced in the developed world. It is a devastating illness whose prevalence increases dramatically with age; first appearing around 40 in some and rising to perhaps 50% of the population to some degree by age 85. (D. Evans, Milbank Q, 1990, 68, 267-289). Alzheimer's disease manifests itself by insidiously destroying memory and leading to mental confusion as nerve cells in the brain are relentlessly lost. The general aging of the population in the coming years will increase the prevalence of the disease and emphasize the need to ameliorate these medical needs before it reaches epidemic proportions.
Research has led to the examination of a variety of drug strategies, largely without success. Early therapeutic strategies include those that were reputed to improve cerebral blood flow or possess psychostimulant abilities. These include the metabolic enhancer dihydroergotoxine, the vasodilators papaverine, isoxsuprine, and cyclandelate, and the psychostimulants methylphenidate and pentylenetetrazol. (W. H. Moos, R. E. Davis, R. D. Schwarz, and E. R. Gamzu, Medicinal Resarch Reviews, Vol. 8, No. 3, 353-391 (1988)). None of these are reported to possess any significant effect upon the disease.
While a variety of classes of therapeutics such as muscarinic receptor agonists, nootropics, nicotinic agonists, m1 agonists and Ca.sup.++ channel blockers are in various stages of development, of greater interest and potential value are the cholinergic agents including acetylcholinesterase inhibitors, acetylcholine release precursors and storage modulators. This `cholinergic deficiency`, hypothesis has dominated research over the past two decades since of all the neurotransmitters, acetylcholine is known to exhibit the greatest decrease in Alzheimer's patients and it has long been connected to learning and memory.
Only two drugs have approval by the FDA for clinical use; the cholinesterase inhibitors Cognex.RTM. (tacrine or tetrahydroaminacrine) and Aricept.RTM. (donepezil). Tacrine has been marketed for several years but its initial promise has largely been unfulfilled (Hollister, L.; Gruber, N. Drugs and Aging 1996, 8, 47-55). However, benefits that were noted with tacrine appear to supply support for the cholinergic hypothesis of Alzheimer's disease. ( M. R. Farlow, Alzhemier Disease and Associated Disorders, 1994,8, Suppl. 2, S50-S57). Donepezil has very recently been granted approval and is still undergoing evaluation in the general population (Kawakami, Y.; Inoue, A.; Kawai, T.; Wakita, M.; Sugimoto, H. Hopfinger, A. J. Bioorganic & Med, Chem. Lett. 1996, 4, 1429-1445).
The DuPont Merck Pharmaceutical Company initiated a major research effort in the early 1980s to identify compounds that enhanced neurotransmitter release. This led to a novel class of compounds highlighted by linopirdine which underwent clinical examination, (review of linopirdine: Chorvat et al. Drugs of the Future 1995, 20(11), 1145-162). Compound I is representative of second generation compounds discovered in this continuing area of research. ##STR1##
International publication WO 94/241131 (Teleha, C. A.; Wilkerson, W. W.; Earl, R. A.) and International publication WO 95/27489 (Saydoff, J., Zaczek, R.) indicate the value of I as a acetylcholine release agent and as possibly useful in the treatment of cognitive and learning disorders. Due to the importance of Compound I in the treatment of cognitive diseases, it is necessary to develop economical and efficient synthetic processes for its production.
The utility of the present invention lies in the discovery of an efficient process that permits the commercial manufacture of a more stable Form 2 polymorph of crystalline I. U.S. Pat. No. 5,594,001 (Teleha, C. A.; Wilkerson, W. W.; Earl, R. A.) teaches that I may be prepared by the initial chlorination of 2-fluoro-4-methylpyridine to the monochloro product followed by its use for the bis-alkylation of anthrone. The process described by Teleha, et al. requires the use of the solvent carbon tetrachloride (expensive, an environmental hazard and a suspected carcinogen) to generate the benzyl chloride. Additionally, repeated column chromatography is necessary to purify the drug. This method is not realistically scalable to multi-kilo preparations.
The present invention provides for a more efficient, nonchromatographic purification process to yield a stable, crystalline product without the use of dangerous, costly materials. The process employs the use of acetonitrile as a safer, more economical alternative to carbon tetrachloride. A significant improvement also stems from the discovery that through the use of catalytic acid, the chlorination is faster and generates less impurities when compared to the same reaction without acid. This result was unexpected in light of the literature which teaches that the use of N-bromosuccinimide in the presence of acid results in ring halogenation as opposed to sidechain halogenation (Bovonsombat and McNelis, Synthesis, 1993, 237-241). The chlorinated product is then converted to the water soluble benzyl alcohol derivative allowing separation from unchlorinated or overchlorinated impurities which are characteristic by-products of such a system. The present invention proceeds through a stable, crystalline mesylate intermediate, which removes the need for chromatographic separation prior to alkylation with anthrone. Dialkylation of anthrone with the mesylate intermediate in the presence of strong base provides the final drug. Recrystallization in alcoholic solvents leads to a more thermodynamically stable polymorph which is extremely advantageous to the commercial scale manufacture of this important compound.